JP5934120B2 - Cyclic sulfonium salt, method for producing the same, and α-glucosidase inhibitor using the same - Google Patents

Description

The present invention relates to a novel cyclic sulfonium salt compound and its pharmaceutical use. More specifically, the present invention contains a novel cyclic sulfonium salt compound having an α-glucosidase inhibitory activity or an isomer, solvate or pharmaceutically acceptable salt thereof, and the compound. The present invention relates to a pharmaceutical composition for inhibiting α-glucosidase, a pharmaceutical composition for preventing or treating diabetes, and an antidiabetic food.

Diabetes is a group of diseases characterized by abnormal glucose homeostasis leading to elevated blood sugar, and is mainly classified into type 1 diabetes (insulin-dependent diabetes) and type 2 diabetes (insulin-independent diabetes). Most of them are type 2 diabetes.

Glucosidases (particularly α-glucosidases), which are glycolytic enzymes, are involved in several important biological processes (eg digestion, glycoprotein biosynthesis, lysosomal catabolism of complex carbohydrates) . Therefore, by using a glucosidase inhibitor that is a substance that inhibits the saccharide-decomposing action of α-glucosidase, digestion and absorption of sugar in the intestine and the like can be suppressed. Therefore, the usefulness of a glucosidase inhibitor as a therapeutic or preventive for diabetes is expected.

In the late 1990s, salacinol having the following structural formula was discovered as a pharmacological essential substance from a medicinal plant, Salacia reticulata, which was used in Indian traditional medicine (Ayur Veda). -It has been reported to have glucosidase inhibitory activity (Patent Document 1, Non-Patent Documents 1 and 2).

In addition to the above-mentioned salacinol, cotaranol, poncolanol and the like have been found as salacinol analogs, and these analogs have also been reported to have glucosidase inhibitory activity (Patent Document 2, Non-Patent Documents 3 and 4). The structure of these natural product-derived substances including salacinol is that the erythritol-like carbon side chain is bonded to the ring sulfur atom of the thiosugar molecule part to form a sulfonium ion, and the sulfonium ion and the carbon side chain are It has a unique structure in which a sulfate anion forms an intramolecular bond to form a spiro skeleton.

Furthermore, from the viewpoint of ease of production or improvement of pharmacological activity, it does not have a sulfate anion on the carbon side chain of salacinol, including a desulfurized ester form (also referred to as neosaracinol) represented by the following structural formula of salacinol. A cyclic onium compound that is a desulfurized ester has been reported (Patent Document 3). These desulfurized ester compounds have an α-glucosidase inhibitory activity equal to or higher than that of natural products, and are excellent from the viewpoint of ease of production such as stability.

Furthermore, 3'-O-methyl neoponcoranol (n = 2) has been recently reported (Non-patent Document 5). In this document, the methyl derivative hardly contributes to the improvement of the α-glucosidase inhibitory activity as compared with natural salacinol, which means that the introduction of an alkyl group or the like into the 3′-position hydroxy group is an α-glucosidase. This suggests that the inhibitory activity cannot be greatly improved.

JP 2002-179673 A JP 2004-323420 A JP 2005-002051 A Yoshikawa, M., Muraoka, O., et al., Tetrahedron Lett., 1997, 38, 8367 Yoshikawa, M., Muraoka, O. et. Al., Bioorg. Med. Chem., 2002, 10, 1547 Yoshikawa, M. et. Al., Chem. Pharm. Bull., 1998, 46, 1339 Yoshikawa, M., Muraoka, O. et.al., Heterocycles, 2008, 75, 1397 Eskandari, R. et. Al., Bioorg. Med. Chem. Lett. 2010, 20, 5686

The present inventors were surprised as a result of continuing earnest research despite the negative suggestion regarding the introduction of the methyl group into the 3′-position hydroxy group in Non-Patent Document 5 above. The introduction of a more hydrophobic group such as an alkyl group, such as an ethyl group having a large carbon number, a cycloalkyl group, an aralkyl group, or a heteroaralkyl group, significantly increases the α-glucosidase inhibitory activity. I found it.

That is, the present inventors have found that 3′-O-alkylated analogs such as salacinol, that is, the cyclic sulfonium salt compound represented by the following structural formula (I) functions as an α-glucosidase inhibitor and diabetics. The present invention was completed by finding it useful as a prophylactic or therapeutic agent.

Therefore, an object of the present invention is to provide a novel cyclic sulfonium salt compound or an isomer, solvate or pharmaceutically acceptable salt thereof useful as an α-glucosidase inhibitor. Another object of the present invention is to provide a pharmaceutical composition for inhibiting α-glucosidase, a pharmaceutical composition for preventing or treating diabetes, and an antidiabetic food.

In order to achieve the above object, the present invention has, as a main form, a general formula (I):

[In the formula, ^{R 1} represents a hydrogen atom or _{- (CH (OH)) n} -CH 2 OH (n is an integer of 0 to 2) means; ^{R 2} is
(I) unsubstituted or substituted _C 1 _{-C 16} alkyl group (where, n excluding methyl group when the 1),
(Ii) unsubstituted or substituted C ₃ -C ₆ cycloalkyl,
(Iii) General formula (Ia): represented by —R ₁ —R ₂ (wherein R ₁ represents a C ₁ -C ₄ alkylene group and R ₂ represents a monovalent aromatic cyclic group). An unsubstituted or substituted aralkyl group, or (iv) general formula (Ia): —R ₃ —R ₄ (wherein R ₃ represents a C ₁ -C ₄ alkylene group, and R ₄ represents a monovalent heterocyclic ring) A hydrophobic group consisting of an unsubstituted or substituted heteroaralkyl group represented by the formula group; and
X ⁻ means a conjugate base ion of Bronsted acid]
Or a stereoisomer , solvate or pharmaceutically acceptable salt thereof.

（式中、Ｒ^１、Ｒ^２およびＸ⁻は、前記と同じ意味を有する）
で表される環状スルホニウム塩化合物もしくはその立体異性体、溶媒和物またはそれらの医薬的に許容し得る塩を提供する。
In a preferred embodiment, the present invention is represented by the general formula (II):

(Wherein R ¹ , R ² and X ⁻ have the same meaning as described above)
Or a stereoisomer , solvate or pharmaceutically acceptable salt thereof.

In the present specification, the term “cyclic sulfonium salt compound or an isomer, solvate or pharmaceutically acceptable salt thereof” may be simply abbreviated as “cyclic sulfonium salt compound”. However, this abbreviation is used for the purpose of simplifying the description of the specification, and unless otherwise specified, other isomers, solvates and / or their pharmaceutically It should be understood that the term is used to encompass all or any of the acceptable salts.

In a preferred embodiment, the present invention is a cyclic sulfonium salt compound (I) or (II), wherein R ¹ is a hydrogen atom, -CH ₂ OH,-(CH ₂ ) ₂ -CH ₂ OH or-(CH ₂ ) A cyclic sulfonium salt compound which is _3- CH ₂ OH is provided.

In a more preferred embodiment of the present invention, the cyclic sulfonium salt compound (I) or (II), wherein R ² is a C ₁ -C ₁₃ alkyl group, or a benzyl group, o-, m- or p-halobenzyl. Group, o-, m- or p-nitrobenzyl group, o-, m- or p-methylbenzyl group, o-, m- or p-trifluoromethylbenzyl group, hydroxymethylbenzyl group, naphthylmethyl group or pyridyl Provided is a cyclic sulfonium salt compound which is a methyl group.

In a preferred embodiment of the present invention, the cyclic sulfonium salt compound (I) or (II), wherein X ⁻ is a halogen ion, R ³ SO ₃ ⁻ (wherein R ³ is unsubstituted or halogen-substituted). A sulfonate ion represented by an alkyl group, or an unsubstituted aryl group or a halogen-substituted or alkyl-substituted aryl group, R ⁴ COO ⁻ (wherein R ⁴ is a hydrogen atom, an unsubstituted or halogen-substituted alkyl group) Or a non-substituted, halogen-substituted or alkyl-substituted aryl group), a sulfate ion, an alkyl sulfate ion, a hydrogen sulfate ion, a perchlorate ion, or a conjugate of a Lewis acid and a hydrogen halide Cyclic sulfonium salt compounds consisting of conjugated base ions of Bronsted acid, which is a base ion To provide.

As a more preferred embodiment of the present invention, there is provided a cyclic sulfonium salt compound (I) or (II), wherein X ⁻ is Cl ⁻ or BF ₄ ^— .

The present invention provides, as another form, a pharmaceutical composition for α-glucosidase inhibition comprising the above cyclic sulfonium salt compound (I) or (II) and a pharmaceutically acceptable carrier.

As another form, the present invention provides diabetes such as type 2 diabetes, diabetic complications, obesity, lipids containing the above cyclic sulfonium salt compound (I) or (II) and a pharmaceutically acceptable carrier. Provided is a pharmaceutical composition for preventing or treating diseases such as metabolic disorders and hypertension.

In still another aspect, the present invention provides α-glucosidase activity in a mammal comprising administering a therapeutically effective amount of the cyclic sulfonium salt compound (I) or (II) to a mammal in need thereof. A method of inhibiting is provided.

In still another aspect, the present invention relates to diabetes and diabetic complications in mammals, comprising administering a therapeutically effective amount of the above cyclic sulfonium salt compound (I) or (II) to a mammal in need thereof. A method for preventing or treating obesity, dyslipidemia, or hypertension is provided.

This invention provides the antidiabetic food containing the said cyclic sulfonium salt compound (I) or (II) as another form.

The cyclic sulfonium salt compounds (I) and (II) according to the present invention are drugs for inhibiting α-glucosidase activity, or prevention or treatment of diabetes, diabetic complications, obesity, dyslipidemia, or hypertension. It is useful as a medicine for

The cyclic sulfonium salt compound according to the present invention has the general formula (I):

[Wherein R ¹ represents a hydrogen atom or — (CH (OH)) _n —CH ₂ OH (n is an integer of 0 to 2);
R ² is
(I) unsubstituted or substituted _C 1 _{-C 16} alkyl group (where, n excluding methyl group when the 1),
(Ii) unsubstituted or substituted C ₃ -C ₆ cycloalkyl,
(Iii) General formula (Ia): represented by —R ₁ —R ₂ (wherein R ₁ represents a C ₁ -C ₄ alkylene group and R ₂ represents a monovalent aromatic cyclic group). An unsubstituted or substituted aralkyl group, or (iv) general formula (Ia): —R ₃ —R ₄ (wherein R ₃ represents a C ₁ -C ₄ alkylene group, and R ₄ represents a monovalent heterocyclic ring) A hydrophobic group consisting of an unsubstituted or substituted heteroaralkyl group represented by the formula group; and
X ^- is meant a conjugate base of a Bronsted acid. ]
Can be expressed as

（式中、Ｒ^１、Ｒ^２およびＸ⁻は上記と同じ意味を有する）
で表すことができる。The cyclic sulfonium salt compound as a preferred embodiment of the present invention has the general formula (II):

(Wherein R ¹ , R ² and X ⁻ have the same meaning as above)
Can be expressed as

In the above general formulas (I) and (II), the term “alkyl group” represented by R ² (i) is linear or branched having 1 to 16 carbon atoms, preferably 1 to 14 carbon atoms. A monovalent saturated aliphatic hydrocarbon group is meant. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a neopentyl group, and a hexyl group. , Heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group and the like, but are not limited thereto.

The alkyl group may have a substituent. Examples of the substituent include a halogen atom such as a chlorine atom and a fluorine atom, a hydroxy group, an amino group, a nitro group, and the like. Is not to be done. The number of substituents is not particularly limited, but is preferably 1 to 3, and the types of substituents may be different.

In the above general formulas (I) and (II), the term “cycloalkyl group” represented by R ² (ii) is a monovalent cyclic saturated aliphatic group having 3 to 6 carbon atoms, preferably 3 to 5 carbon atoms. It means a hydrocarbon group, and specific examples include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.

The cycloalkyl group may have a substituent, and the substituent is the same as the substituent of the alkyl group in the general formula (I), for example, a halogen such as a chlorine atom or a fluorine atom. Examples include, but are not limited to, atoms, hydroxy groups, amino groups, nitro groups, and the like. The number of substituents is not particularly limited, but is preferably 1 to 3, and the types of substituents may be different.

In the term “aralkyl group” represented by the above general formula R ² (iii), the term “C ₁ -C ₄ alkylene group” represented by R ₁ is a straight chain having 1 to 4 carbon atoms or It means a branched divalent saturated aliphatic hydrocarbon group, and examples thereof include a methylene group, an ethylene group, a propylene group, a butylene group, and a methylethylene group. The term “aryl group” represented by R ₂ means a monovalent aromatic cyclic group, and examples thereof include a phenyl group and a naphthyl group. In the aryl group, one or more, preferably 1 to 3 identical or different substituents may be present at any position. Examples of the substituent include a chlorine atom, a bromine atom, and fluorine. halogen atoms such as atoms, hydroxy group, nitro group, methyl group, _C 1 -C ₃ alkyl group such as ethyl groups, _C 1 -C ₃ haloalkyl group such as trifluoromethyl groups, _C 1 -C such as hydroxymethyl group ₃ hydroxyalkyl group etc. are mentioned.

Accordingly, examples of the aralkyl group include benzyl groups, o-, m-, p-chlorobenzyl groups, halobenzyl groups such as o-, m-, p-bromobenzyl groups, o-, m-, p-nitrobenzyl. Nitrobenzyl group such as o-, m-, p-methylbenzyl group, alkylbenzyl group such as o-, m-, p-trifluorobenzyl group, o-, m-, p -Hydroxyalkylbenzyl groups such as hydroxymethylbenzyl group.

In the term "heteroaralkyl group" represented by the above general formula ^R 2 (iv), the term represented by _{R 3 "C} 1 -C ₄ alkylene group", the term _{"C 1} represented by _{R 1} - It has the same meaning as “C ₄ alkylene group”.

In the general formula R ² (iv), the “heteroaryl group” represented by R ₄ is a monovalent heterocyclic group, and is selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring. A 5- to 6-membered monocyclic group having at least 1, preferably 1 to 3 heteroatoms as ring members, and a polycyclic group (for example, a bicyclic group) bonded in a condensed ring manner, and It means a hydroheterocyclic group such as dihydro, tetrahydro, hexahydro and the like. Further, the heteroatoms of the heteroaryl group may be the same or different. Examples of such heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridyl, furyl, thienyl, oxadiazolyl, oxaazepinyl, azepinyl , Pyrazinyl group, pyrimidinyl group, pyridazinyl group, triazinyl group, triazolyl group and the like monocyclic heteroaryl group; and benzothiazolyl group, benzoxazolyl group, benzothienyl group, benzofuryl group, quinolinyl group, quinolinyl-N-oxide group, isoquinolinyl Group, isoquinolinyl-N-oxide group, benzimidazolyl group, benzopyranyl group, indolizinyl group, cinnolinyl group, quinoxalinyl group, indazolyl group, pyrrolopyridyl group, flopi Dinyl group, benzoisothiazolyl group, benzoisoxazolyl group, benzodiazinyl group, benzothiopyranyl group, benzotriazolyl group, benzopyrazolyl group, naphthyridinyl group, phthalazinyl group, purinyl group, pyridopyridyl group, quinazolinyl group, Examples thereof include, but are not limited to, bicyclic heteroaryl groups such as thienofuryl group, thienopyridyl group, and thienothienyl group, and dihydroheteroaryl groups and tetrahydroheteroaryl groups thereof. In the heteroaryl group, one or more, preferably 1 to 3 identical or different substituents may be present at any position. Examples of the substituent include a chlorine atom, a bromine atom, halogen atom such as a fluorine atom, hydroxy group, nitro group, methyl group, _C 1 -C ₃ alkyl group such as ethyl group, _C 1 -C ₃ haloalkyl group such as trifluoromethyl group, _{C 1} such as a hydroxymethyl group - such as C ₃ hydroxyalkyl groups.

In the above general formulas (I) and (II), the counter anion represented by X ⁻ means an anion that serves as a counter ion for the sulfonium ion, specifically, a conjugate base of Bronsted acid. Means. Here, examples of the Bronsted acid include hydrogen halides such as hydrogen chloride and hydrogen bromide; monoalkyl esters such as sulfuric acid and monomethyl sulfuric acid and monoethyl sulfuric acid; methanesulfonic acid, ethanesulfonic acid, chlorosulfonic acid, and fluorosulfone. Acids, benzenesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid, dinitrobenzenesulfonic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid, perfluorobutanesulfonic acid, trifluoroethanesulfonic acid and other sulfonic acids; carboxylic acid trifluoroacetic acid , trihalo carboxylic acids such as trichloroacetic _{acid; HBF 4, HPF 6, HSbF} 4, HSbF 6, HAsF 6, hBCl 4, hBCl 3 F, HSbCl 6, HSbCl 5 Lewis acids such as F and a hydrogen halide It can be exemplified Bronsted acid strong acidity such compounds.

Accordingly, examples of Bronsted acid conjugate bases include halogen ions, sulfate ions, hydrogen sulfate ions, alkyl sulfate ions, perchlorate ions, R ³ SO ₃ ⁻ (wherein R ³ is unsubstituted or halogen-substituted). A sulfonate ion represented by an alkyl group, or an unsubstituted or halogen / alkyl-substituted aryl group, R ⁴ OSO ₃ ^— (wherein R ⁴ represents an unsubstituted or halogen-substituted alkyl group, an unsubstituted or An alkyl sulfate ion represented by an alkyl / halogen-substituted aryl group, and R ⁵ COO ⁻ (wherein R ⁵ represents a hydrogen atom, an unsubstituted or halogen-substituted alkyl group, or an unsubstituted or alkyl / halogen-substituted group). A carboxylate ion represented by an aryl group) or the above Lewis acid and halogen It includes ions of such a conjugate base of a compound consisting of hydrogen.

Further, specific examples include halogen ions (for example, F ⁻ , Cl ⁻ , Br ^{− and the} like); sulfonate ions (for example, CH ₃ SO ₃ ⁻ , C ₂ H ₅ SO ₃ ⁻ , CF ₃ SO ₃ ⁻ , p _{-CH 3 C 6 H 4 SO 3} - , etc.), alkyl sulfate ion _{^{(e.g., CH 3 OSO 3 -, C}} 2 H 5 OSO 3 -, CF 3 OSO 3 -, p-CH 3 C 6 H 5 OSO 3 - Carboxylate ion (for example, HCOO ⁻ , CH ₃ COO ⁻ , CF ₃ COO ⁻ , C ₆ H ₅ COO ⁻ etc.); phosphate ion, monohydrogen phosphate ion, dihydrogen phosphate ion; ClO ₄ ⁻ Examples include, but are not limited to, a conjugate base of a compound comprising a Lewis acid and a hydrogen halide (for example, BF ₄ ⁻ , PF ₆ ^{— and the} like). Of these, X ⁻ is particularly preferably Cl ⁻ and BF ₄ ^— .

In the definition of the Bronsted acid conjugate base, the term “halogen-substituted alkyl group” refers to the alkyl group substituted with one or more halogen atoms (for example, chlorine atom, bromine atom, fluorine atom, etc.). I mean. Similarly, the term “halogen / alkyl-substituted aryl group” refers to the above aryl group substituted with one or more halogen atoms (eg, chlorine atom, bromine atom, fluorine atom, etc.) and / or the above alkyl group. I mean.

The definitions of the terms in the above are similarly applied in the following description unless otherwise specified.

（式中、Ｒ^１、Ｒ^２およびＸ⁻は上記と同じ意味を有する）
で表されるように、チオ糖５員環部分の環内硫黄原子上にポリヒドロキシ炭化水素鎖が結合し、またチオ糖５員環の環内硫黄原子上のスルホニウムイオン:Ｓ^＋が対陰イオンであるＸ⁻と塩を形成する構造を有することを特徴としている。In the present invention, the cyclic sulfonium salt compound has the general formula (I):

(Wherein R ¹ , R ² and X ⁻ have the same meaning as above)
As shown in the formula, a polyhydroxy hydrocarbon chain is bonded to the ring sulfur atom of the thiosaccharide 5-membered ring moiety, and the sulfonium ion: S ⁺ on the ring sulfur atom of the thiosugar 5-membered ring It is characterized by having a structure that forms a salt with X ⁻ that is an ion.

（式中、Ｒ^１、Ｒ^２およびＸ⁻は上記と同じ意味を有する）
に示すように、チオ糖５員環部分ならびに硫黄原子上のポリヒドロキシ炭化水素鎖上の各置換基は立体配置している。The cyclic sulfonium salt compound of the present invention has the general formula (II):

(Wherein R ¹ , R ² and X ⁻ have the same meaning as above)
As shown in FIG. 2, the thiosaccharide 5-membered ring moiety and each substituent on the polyhydroxy hydrocarbon chain on the sulfur atom are arranged in a steric configuration.

That is, in the above general formula (II), the configuration at the 3 ′ position to which the OR ² group is bonded may be either R or S configuration. In addition, a hydroxy group may be substituted at the 4 ′ to 6 ′ position of the hydrocarbon chain portion represented by the R ¹ group. In this case, the configuration of the hydroxy substituent at the 4 ′ position is R Each configuration of the hydroxy substituents at the 5 ′ to 6 ′ positions may be either R or S. Therefore, there are various stereoisomers depending on the combination of configuration choices at each carbon position. Stereoisomers include diastereomers, and all these isomers and mixtures thereof are intended to be included within the scope of the present invention.

で表わすとおりである。この化合物は、一般にネオサラシノール（neosalacinol）と呼称されている。なお、参考までに、一般式（ＩＩａ）において、３^’位の−ＯＨが−ＯＳＯ_３ ⁻である誘導体はサラシノール（salacinol）と呼称されている。Further, an example of the configuration of each substituent of the cyclic sulfonium salt compound (II) will be described in detail. When R ¹ group is — (CH (OH) n—CH ₂ OH and n is 0 The configuration of each substituent is represented by the general formula (IIa):

As shown. This compound is commonly referred to as neosalacinol. For reference, in general formula (IIa), a derivative in which —OH at the 3 ^′ position is —OSO ₃ ^— is referred to as salacinol.

で表わすとおりであり、一般にネオポンコラノール（neoponkoranol）と呼称されている。なお、参考までに、一般式（ＩＩｂ）において、３^’位の−ＯＨが−ＯＳＯ_３ ⁻である誘導体は、一般にポンコラノール（ponkoranol）と呼称されている。The configuration of the bonding position of each hydroxy substituent of the cyclic sulfonium salt compound in which the R ¹ group is — (CH (OH)) ₂ —CH ₂ OH is represented by the general formula (IIb):

And is generally referred to as neoponkoranol. For reference, in general formula (IIb), a derivative in which —OH at the 3 ^′ position is —OSO ₃ ^— is generally referred to as ponkoranol.

で表わすとおりであり、一般にネオコタラノール（neokotalanol）と呼称されている。なお、参考までに、一般式（ＩＩｂ）において、３^’位の−ＯＨが−ＯＳＯ_３ ⁻である誘導体は、一般にコタラノール（kotalanol）と呼称されている。Furthermore, the configuration of the bonding position of each hydroxy substituent of the cyclic sulfonium salt compound in which the R ¹ group is — (CH (OH)) ₃ —CH ₂ OH is represented by the general formula (IIc):

And is generally referred to as neokotalanol. For reference, in general formula (IIb), a derivative in which —OH at the 3 ^′ position is —OSO ₃ ^— is generally referred to as kotalanol.

Further, the cyclic sulfonium salt compound (I, II) of the present invention (hereinafter also referred to as the present compound) includes its solvate. Here, the “solvate” means a compound in which molecules of a pharmaceutically acceptable solvent are coordinated with the compound of the present invention. Examples of such solvates include hydrates, alcohol solvates, aprotic polar organic solvates, and the like, and hydrates, ethanol solvates, dimethyl sulfoxide solvates and the like are preferable. Such solvates can be obtained according to known methods.

The compound of the present invention can also be used as a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt may be any salt as long as it forms a pharmaceutically acceptable salt with the compound of the present invention. Examples thereof include salts with inorganic acids, organic acids, amino acids and the like. Can be mentioned. Such a pharmaceutically acceptable salt can be obtained by reacting the compound of the present invention with an inorganic base, an organic base, an inorganic acid, an organic acid, or an amino acid according to a known method.

Examples of the inorganic acid include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like. Examples of organic acids include oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, glucuronic acid, ascorbic acid, methanesulfonic acid, and benzenesulfone. An acid, p-toluenesulfonic acid, etc. are mentioned. Examples of amino acids include lysine, arginine, aspartic acid, glutamic acid and the like.

Although the manufacturing method of cyclic sulfonium salt compound (I) and (II) based on this invention is demonstrated easily below, it is not limited to these manufacturing methods at all.

The cyclic sulfonium salt compounds (I) and (II) of the present invention can be produced by a conventional method, for example, according to the following reaction formula. In addition, the compound to be used is protected by a protective group as necessary, and deprotected in a later step, or converted into a desired functional group using the functional group as a precursor. It is good to use. In addition, isolation and purification of the obtained product can be performed by appropriately selecting a commonly used method such as crystallization, recrystallization, distillation, liquid separation, silica gel chromatography, preparative HPLC, etc., if necessary. However, depending on the case, it can also proceed to the next step without isolation and purification.

In the present invention, a general method for producing a cyclic sulfonium salt compound when the R ¹ group means — (CH (OH) n—CH ₂ OH (where n is 0) is as follows.

First, one of the hydroxyl groups of the starting diol compound (1) is protected using a (cyclo) alkylation or (hetero) aralkylation reagent, and the terminal O-protected compound (2) and the internal O-protected are protected. Two kinds of compounds (3) are obtained.

Next, the obtained terminal O-protected compound (2) is reacted with a (cyclo) alkylating reagent such as halogenated (cyclo) alkyl to (hydroxy) alkylate the hydroxy group to give the corresponding ether compound (4). ) Next, the compound (5) is obtained by deacetonidation of the ether compound (4). Next, the obtained compound (5) is epoxidized to obtain an epoxy compound (8) -A (wherein R is an alkyl group or a cycloalkyl group).

On the other hand, by reacting the obtained compound (2) with a (hetero) aralkylation reagent such as a halogenated (hetero) aralkyl, the hydroxy group is (hetero) aralkylated to give the corresponding ether compound (6). Get. As for the obtained ether compound (6), a compound (7) is obtained by deacetonidation. Epoxy compound (8) -B (wherein OY is a (hetero) aralkyl group) is obtained by epoxidizing this compound (7).

On the other hand, when the hydroxyl group of the starting diol compound (1) is protected with a (hetero) aralkylating reagent such as a halogenated (hetero) aralkyl, the compound (3) is obtained. Next, the remaining terminal primary hydroxy group is protected with an appropriate protecting group (P) to give compound (6). Compound (6) can be led to epoxy compound (8) -B as described above (where OY is a (hetero) aralkyl group).

  Next, the epoxy compound (8) -A and the epoxy compound (8) -B obtained in the reaction formula 1 are subjected to a coupling reaction with the thiosaccharide compound (9) -A according to the following reaction formula 2-A. S-alkylation can lead to the cyclic sulfonium salt compound (10) -A. When the protecting group of the obtained cyclic sulfonium salt compound (10) -A is deprotected, the target compound (I) -A is obtained.

That is, as shown in Reaction Formula 2-A, the epoxy compound (8) -A obtained in Reaction Formula 1 is S-alkylated by a coupling reaction with the thiosaccharide compound (9) -A, and the cyclic sulfonium salt compound (10) -A is obtained. Subsequently, by removing the protecting groups (P and P ′), the cyclic sulfonium salt compound represented by the formula (I) -A which is a compound of the present invention (where R is a (cyclo) alkyl group or ( A hetero) aralkyl group). Further, after any step of the above reaction formula, X ⁻ can be converted by performing an anion exchange reaction with an anion exchange resin as necessary.

Next, a general method for producing a cyclic sulfonium salt compound in the case where the R ¹ group is — (CH (OH) n—CH ₂ OH (where n means 1 to 3) is as follows. .

First, as shown in Reaction Scheme 3, one protected hydroxy group (P) of the sugar derivative (11) as a starting material is changed to a (cyclo) alkyl group (R) or a (hetero) aralkyl group (Y). To obtain the compound (12). Furthermore, the terminal O-protecting group (P) is converted into a leaving group (P ′) to obtain a sugar derivative (13).

  Next, the sugar derivative (13) obtained in Reaction Scheme 3 is coupled with a thiosaccharide compound as shown in Reaction Formula 2-B, and then is subjected to a protective group elimination and reduction step. A cyclic sulfonium salt compound can be obtained.

More specifically, as shown in Reaction Formula 2-B, the sugar derivative (13) produced in Reaction Formula 3 is S-alkylated by a coupling reaction with the thiosugar compound (9) -B to form a cyclic sulfonium salt compound. (10) -B is obtained. Next, after removing protecting groups (P and) and (P ′ and) to obtain compound (14) -B, the obtained cyclic sulfonium salt compound (14) -B is reduced, whereby A cyclic sulfonium salt compound ((I) -B) can be obtained. Here, the group corresponding to R is a (cyclo) alkyl group, and the group corresponding to Y is a (hetero) aralkyl group. After any step of the above reaction formula, anion exchange can be performed with an anion exchange resin as necessary.

Incidentally, X ^- type conjugate base of Brønsted acid represented by is not intended to be otherwise limiting in terms of pharmacokinetic aspects and manufacturability. Anion conversion can be easily performed by using an anion exchange resin or acid reagent widely used in organic synthesis.

Since the cyclic sulfonium salt compound (I, II) of the present invention or its isomer, solvate or pharmaceutically acceptable salt thereof can inhibit the action of α-glucosidase, digestive absorption of carbohydrates Can be delayed, and postprandial hyperglycemia can be improved / suppressed. Therefore, the cyclic sulfonium salt compound of the present invention is useful for prevention or treatment of diseases involving α-glucosidase.

Diseases involving α-glucosidase are metabolic diseases and metabolism-related disorders and include, for example, diabetes and / or diabetic complications. Specifically, examples of such diseases include type 1 diabetes, type 2 diabetes, dyslipidemia, postprandial dyslipidemia, impaired glucose tolerance (IGT), fasting plasma glucose abnormal, obesity, Examples include, but are not limited to, diabetic retinopathy, cataract, diabetic nephropathy, hypertension, diabetic neuropathy and insulin resistance. Preferred examples include diabetes, obesity or dyslipidemia, and particularly preferred is type 2 diabetes.

  The compound of the present invention can be formulated as a pharmaceutical composition with a pharmaceutically acceptable carrier according to a method known per se in the technical field of pharmaceutical formulation. The pharmaceutical composition according to the present invention can be administered orally or parenterally. Examples of the pharmaceutical composition for oral administration include tablets, capsules, granules, powders, troches, syrups, emulsions, suspensions and the like. In addition, examples of the pharmaceutical composition for parenteral administration include external preparations, suppositories, injections, eye drops, and nasal preparations. The content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight, preferably 0.1 to 70% by weight of the whole composition It is good.

Examples of the pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials, such as excipients, disintegrants, binders, fluids in solid formulations. Examples include agents, lubricants, etc., solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers or pH adjusters, and soothing agents. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, refreshing agents or flavoring agents, antifoaming agents, thickeners and the like are used as necessary.

Examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, Examples include gum arabic. Examples of the disintegrant include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, and crystalline cellulose. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like. Examples of the fluidizing agent include light anhydrous silicic acid and magnesium stearate. Examples of the lubricant include magnesium stearate, calcium stearate, talc and the like.

    Examples of the solvent include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the solubilizer include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate and the like. Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, D-mannitol and the like. Examples of the buffering agent or pH adjusting agent include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like. Examples of soothing agents include benzyl alcohol.

Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like. Examples of the antioxidant include sodium sulfite and ascorbic acid. Examples of the colorant include food dyes (eg, food red No. 2 or No. 3, food yellow No. 4 or No. 5, etc.), β-carotene and the like. Examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like. Examples of the refreshing agent or flavoring agent include 1-menthol or mint water. Examples of the antifoaming agent include dimethylpolysiloxane or silicon antifoaming agent. Examples of the thickening agent include xanthan gum, tragacanth, methylcellulose, and dextrin.

The pharmaceutical composition of the present invention can be administered not only to humans but also to pet animals such as dogs and cats. The dose varies depending on the administration subject, disease, symptom, dosage form, administration route, etc. For example, the dose of the present invention, which is orally administered to an adult diabetic patient (body weight: about 60 kg), is an active compound. As a rule, it is usually in the range of about 1 mg to 1 g per day. These amounts can be administered once or in several divided doses.

The pharmaceutical composition according to the present invention can be used as a combined pharmaceutical composition in combination with one or more other drugs (hereinafter also referred to as concomitant drugs) by a method generally performed in the pharmaceutical field. . The combined pharmaceutical composition may be administered as a combination preparation containing the compound of the present invention and the concomitant drug in the same preparation, or both preparations may be administered simultaneously or separately at regular intervals. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, disease, symptom, dosage form, administration route, administration time, combination and the like. The administration form of the concomitant drug is not particularly limited as long as the compound of the present invention or a salt thereof and the concomitant drug are combined.

Examples of concomitant drugs that can be used as the combination pharmaceutical composition of the present invention include antidiabetic drugs, antiobesity drugs, antilipidemia drugs, and hypertension drugs.

  Anti-diabetic drugs include, for example, hypoglycemic drugs, anti-diabetic complication drugs, and the like. Examples of such antidiabetic agents include insulin preparation (injection), fructose-1,6-bisphosphatase (FBPase) inhibitor, glucagon receptor antagonist, glucocorticoid receptor antagonist, glucokinase activator, Glutamine fructose-6-phosphate aminotransferase (GFAT) inhibitor, glycogen phosphorylase (GP) inhibitor, glycogen synthase kinase 3 (GSK-3) inhibitor, GPR40 agonist, phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, protein Tyrosine phosphatase 1B (PTPase 1B) inhibitor, pyruvate dehydroxygenase kinase (PDHK) inhibitor, SGLUT inhibitor, SH2 domain-containing inositol phosphatase 2 (SHIP2) inhibitor, dipeptidyl peptidase IV (DPP-IV) inhibitor, tGLP-1 peptide analog Α-glucosidase inhibitor, insulin sensitivity enhancer, sulfonylurea receptor agonist (SU agent), immediate-acting insulin secretagogue (nateglinide), low-molecular tGLP-1 receptor agonist, low-molecular insulin oral agent, biguanite agent, 11β -HSD-1 inhibitor, adiponectin receptor agonist, AMP-activated protein kinase (AMPK) activator, PPARγ receptor agonist / antagonist, β3 adrenergic receptor agonist and the like. Antidiabetic complication drugs include, for example, final glycation reaction product (AGE) production inhibitor, aldose reductase inhibitor, angiotensin II receptor antagonist, angiotensin converting enzyme (ACE) inhibitor, protein kinase Cβ ( PKCβ) inhibitors and the like.

Anti-obesity agents include, for example, acetyl-CoA carboxylase 1 (ACC1) inhibitor, acetyl-CoA carboxylase 2 (ACC2) inhibitor, bombesin receptor subtype 3 (BRS-3) agonist, diacylglycerol acyltransferase (DGAT) ) Inhibitors, glucose-dependent insulin secretagogue polypeptide (GIP) receptor antagonists, leptin receptor agonists, melanocortin (MC) receptor agonists, neuropeptide Y5 (NPY5) receptor antagonists, perilipin inhibitors, uncoupling proteins (UCP) inducers / activators, 11β-HSD-1 inhibitors, adiponectin receptor agonists, AMP-activated protein kinase (AMPK) activators, PPARγ receptor agonists / antagonists, β3 adrenergic receptor agonists, etc. Can be mentioned.

Examples of antilipid metabolic disorders include apolipoprotein A1 (Apo-A1) inducer, cholesteryl ester transfer protein (CETP) inhibitor, endothelial lipase inhibitor, HMG-CoA reductase inhibitor, lipoprotein lipase (LPL) ) Activators, microsomal triglyceride transfer protein (MTP) inhibitors, PPARα receptor agonists, PPARδ receptor agonists and the like.

  Examples of antihypertensive agents include α blockers, β blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), calcium antagonists, renin inhibitors and the like.

  The cyclic sulfonium salt compound (I, II) or an isomer, solvate or pharmaceutically acceptable salt thereof according to the present invention is used for anti-diabetes, anti-diabetic complications, anti-obesity, anti-lipid metabolism disorders. Or foods for prevention or treatment for antihypertension, particularly antidiabetic foods, antiobesity foods, and the like. Therefore, the food of the present invention is useful as a health food such as a functional food.

In the food according to the present invention, conventional additives can be used depending on the type of food. Examples of additives include the above-mentioned excipients, pH adjusters, cooling agents, suspending agents, antifoaming agents, thickening agents, solubilizing agents, disintegrating agents, binders, lubricants, and coloring agents. Or a flavoring agent. In addition, the food of the present invention can be mixed with other physiologically active ingredients, minerals, vitamins, hormones, nutritional ingredients, fragrances and other additives as necessary.

The food of the present invention can be processed by methods commonly used in the form of, for example, capsules such as solutions, hard capsules, soft capsules, tablets, pills, granules, etc., for example, snacks, biscuits, cookies, etc. Can be eaten as confectionery, soft drinks, juices, etc.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
An example of a specific method for producing the compound of the present invention is shown in the following reaction formulas 4 and 5.

(Reaction Formula 4)

(Reaction Formula 5)

In the above reaction formula and the following examples, the abbreviations have the following meanings.
Me is a methyl group, Et is an ethyl group, Bn is a benzyl group, AcOH is acetic acid, DMF is N, N-dimethylformamide, DEAD is diethyl azodicarboxylate, PMBCl is paramethoxybenzyl chloride, aq. Means aqueous solution or aqueous solution, respectively.

The compound was confirmed by analysis of various spectroscopic analyses. Specifically, one-dimensional and two-dimensional proton and carbon 13 nuclear magnetic resonance spectra ( ¹ H NMR, ¹³ C NMR), infrared absorption spectrum (IR), mass spectrum (MS) (for example, fast atom bombardment mass spectrometry) (FABMS) and fast atom bombardment type high resolution mass spectrometry (FABHRMS)), and analysis of specific rotation. Tetramethylsilane was used as an internal standard for the ¹ H nuclear magnetic resonance spectrum in deuterated chloroform. The ¹³ C nuclear magnetic resonance spectrum was based on the following signals: deuterated chloroform: 77.0 ppm and deuterated methanol: 49.0 ppm.

Example 1
1-O-benzyl-3,4-O-isopropylidene-D-erythritol compound (12) and 2-O-benzyl-3,4-O-isopropylidene-D-erythritol compound (13) (Scheme 4)
First, according to a known production method (Abushanab E .; Vemishetti P .; Leiby RW; Singh HK; Mikkilineni AB; Wu DC-J .; Saibaba R .; Panzica, RPJ Org. Chem. 1988, 53, 2598) A diol compound (3,4-O-isopropylidene-D-erythritol) (11) is obtained from isoascorbic acid, and the obtained compound (11) (6 g, 37.0 mmol) is converted into Bu ₂ Sn (IV) O ( A mixture of 11.1 g, 44.6 mmol) and toluene (60 mL) was heated to reflux for 1 hour. The reaction mixture was then concentrated under reduced pressure in an eggplant flask equipped with a Dean-Stark condenser. To the residue was added DMF (60 mL), cesium fluoride (8.5 g, 55.9 mmol) and benzyl bromide (6.6 mL, 55.6 mmol) and the resulting suspension was heated at 60 ° C. for 1 hour. did. After cooling, the reaction mixture was diluted with diethyl ether (200 mL), and then insoluble material was removed by filtration and washed with diethyl ether. The filtrate and washings were combined and made alkaline by adding 10% aqueous sodium hydroxide (100 mL). Subsequently, the precipitated gel was removed by filtration through celite and washed with diethyl ether. The separated organic layer was washed with saturated brine and concentrated to give a pale yellow oil (11.3 g). This was purified by column chromatography (n-hexane: AcOEt, 10: 1 → 5: 1 → 1: 1) to obtain compound (12) (8.5 g, 91%) and compound (13) (651 mg, 7%). )was gotten.

(Example 2)
3,4-O-isopropylidene-1-O-paramethoxybenzyl-D-erythritol compound (14) and 3,4-O-isopropylidene-2-O-paramethoxybenzyl-D-erythritol compound (15) ( Reaction formula 4)
3,4-O-isopropylidene-D-erythritol compound (11) (500 mg, 3.1 mmol), Bu ₂ SnO by a method substantially similar to the synthesis of compounds (12) and (13) in Example 1. A mixture of (920 mg, 3.7 mmol) and toluene (5 mL) was heated to reflux for 1 hour and the reaction mixture was concentrated under reduced pressure. DMF (60 mL), cesium fluoride (8.5 g, 55.9 mmol) and paramethoxybenzyl chloride (0.63 mL, 4.6 mmol) were sequentially added to the residue to obtain a suspension at 60 ° C. for 12 hours. Heated. After the reaction mixture was diluted with diethyl ether (40 mL), the resulting mixture was treated with 10% aqueous sodium hydroxide (pH> 11). The precipitated gel was removed by celite filtration and washed with diethyl ether. The organic layer separated from the combined filtrate and washings was washed with saturated brine and concentrated to give a pale yellow oil (1.22 g). This was purified by column chromatography (n-hexane: AcOEt, 10: 1 → 5: 1 → 1: 1) to obtain compound (14) (730 mg, 89%) and compound (15) (53 mg, 6.5). %).

(Example 3)
1-O-benzyl-2-O-methyl-3,4-O-isopropylidene-D-erythritol compound (16a) (Scheme 4)
A solution of compound (12) (2.0 g, 7.94 mmol) in DMF (10 mL) was added to sodium hydride (476 mg, 11.9 mmol, 60% in liquid paraffin), methyl iodide (1 mL, 16 mmol) and DMF (10 mL). ) Was added dropwise at 0 ° C. After stirring for 1 hour at 0 ° C., the mixture was poured into ice-water (100 mL) and extracted with a mixture of n-hexane and diethyl ether (v / v, 1/1). The extract was washed with saturated brine and concentrated to give a colorless oil of 1-O-benzyl-2-O-methyl-3,4-O-isopropylidene-D-erythritol compound (16a) (2 .31 g) was obtained. The obtained compound was purified by column chromatography (n-hexane: AcOEt, 10: 1) to obtain the title compound (16a) (2.04 g, 97%).

Example 4
1-O-benzyl-2-O-ethyl-3,4-O-isopropylidene-D-erythritol compound (16b) (Scheme 4)
In a manner substantially analogous to the synthesis of compound (16a), from compound (12) (2.0 g, 7.94 mmol) and ethyl iodide (1.27 mL, 15.9 mmol), 1-O-benzyl-2 -O-ethyl-3,4-isopropylidene-D-erythritol compound (16b) (2.13 g, 96%) was obtained as a colorless oil.

(Example 5)
1-O-benzyl-2-O-pentyl-3,4-O-isopropylidene-D-erythritol compound (16c) (Scheme 4)
In substantially the same manner as the synthesis of compound (16a), from compound (12) (900 mg, 3.57 mmol) and 1-bromopentane, 1-O-benzyl-2-O-pentyl-3,4-O -Isopropylidene-D-erythritol compound (16c) (1.1 g, 96%) was obtained.

(Example 6)
1-O-benzyl-2-O-heptyl-3,4-O-isopropylidene-D-erythritol compound (16d) (Scheme 4)
In substantially the same manner as the synthesis of compound (16a), from compound (12) (500 mg, 1.98 mmol) and 1-bromoheptane, 1-O-benzyl-2-O-heptyl-3,4-O was obtained. -Isopropylidene-D-erythritol compound (16d) (673 mg, 97%) was obtained.

(Example 7)
1-O-benzyl-2-O-tridecyl-3,4-O-isopropylidene-D-erythritol compound (16e) (Scheme 4)
In a manner substantially analogous to the synthesis of compound (16a), from compound (12) (800 mg, 3.17 mmol) and 1-bromotridecane (2.4 mL, 9.4 mmol), 1-O-benzyl-2 -O-tridecyl-3,4-O-isopropylidene-D-erythritol compound (16c, 1.19 g, 86%) was obtained.

(Example 8)
1-O-benzyl-2-O-neopentyl-3,4-O-isopropylidene-D-erythritol compound (16f) (Scheme 4)
The title compound (16f, 409 mg, 40%) was obtained from the compound (12) (800 mg, 3.17 mmol) and 1-bromoneopentane by a method substantially similar to the synthesis of the compound (16a).

Example 9
Production method A: 2-O-benzyl-3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -D-erythritol compound (16 g) (Scheme 4)
The title compound (16 g, 425 mg, 96%) was obtained from the compound (13) (300 mg, 1.19 mmol) and p-methoxybenzyl bromide by a method substantially similar to the synthesis of the compound (16a).

(Example 10)
Production method B: 2-O-benzyl-3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -D-erythritol compound (16 g) (Scheme 4)
The title compound (16 g, 387 mg, 98%) was obtained as a colorless oil from the compound (14) (300 mg, 1.06 mmol) and p-methoxybenzyl bromide in substantially the same manner as the synthesis of the compound (16a). It was. The results of ¹ HNMR and ¹³ CNMR of the present compound were consistent with the compound obtained in Example 9.

(Example 11)
3,4-O-isopropylidene-2-O- (o-methylbenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (16h) (Scheme 4)
Compound (14) (150 mg, 0.53 mmol) was o-methylbenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16h, 176 mg, 86%) as a colorless oil. .

(Example 12)
3,4-O-isopropylidene-2-O- (m-methylbenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (16i) (Scheme 4)
Compound (14) (150 mg, 0.53 mmol) was m-methylbenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16i, 200 mg, 98%) as a colorless oil. .

(Example 13)
3,4-O-isopropylidene-2-O- (p-methylbenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (16j) (Scheme 4)
Compound (14) (150 mg, 0.53 mmol) was p-methylbenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16j, 200 mg, 98%) as a colorless oil. .

(Example 14)
3,4-O-isopropylidene-2-O- (o-chlorobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (16k) (Scheme 4)
Compound (14) (300 mg, 1.06 mmol) was o-chlorobenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16k, 397 mg, 92%) as a colorless oil. .

(Example 15)
3,4-O-isopropylidene-2-O- (m-chlorobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (161) (Scheme 4)
Compound (14) (400 mg, 1.42 mmol) was m-chlorobenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (161, 518 mg, 90%) as a colorless oil. .

(Example 16)
3,4-O-isopropylidene-2-O- (p-chlorobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (16m) (Scheme 4)
Compound (14) (257 mg, 0.91 mmol) was p-chlorobenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16 m, 336 mg, 91%) as a colorless oil. .

(Example 17)
3,4-O-isopropylidene-2-O- (o-bromobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (16n) (Scheme 4)
Compound (14) (282 mg, 1.0 mmol) was o-bromobenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16n, 432 mg, 96%) as a colorless oil. .

(Example 18)
3,4-O-isopropylidene-2-O- (m-bromobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (16o) (Scheme 4)
Compound (14) (275 mg, 0.98 mmol) was m-bromobenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16o, 430 mg, 98%) as a colorless oil. .

(Example 19)
3,4-O-isopropylidene-2-O- (p-bromobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (16p) (Scheme 4)
Compound (14) (314 mg, 1.11 mmol) was p-bromobenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16p, 492 mg, 98%) as a colorless oil. .

(Example 20)
3,4-O-isopropylidene-1-O- (o-methoxybenzyl) -2-O- (o-trifluoromethylbenzyl) -1-D-erythritol compound (16q) (Scheme 4)
Compound (14) (400 mg, 1.42 mmol) was o-trifluoromethylbenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16q, 600 mg, 96%) as a colorless oil. Obtained.

(Example 21)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (m-trifluoromethylbenzyl) -1-D-erythritol compound (16r) (Scheme 4)
Compound (14) (275 mg, 0.97 mmol) was m-trifluoromethylbenzylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16r, 412 mg, 96%) as a colorless oil. Obtained.

(Example 22)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (p-trifluoromethylbenzyl) -1-D-erythritol compound (16s) (Scheme 4)
In substantially the same manner as the synthesis of compound (16a), compound (14) (200 mg, 0.71 mmol) was p-trifluoromethylbenzylated to give the title compound (16s, 302 mg, 97%) as a colorless oil. Obtained.

(Example 23)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (o-nitrobenzyl) -D-erythritol compound (16t) (Scheme 4)
A mixture of compound (14) (450 mg, 1.59 mmol), sodium hydroxide (750 mg, 18.8 mmol), water (4 ml) and dichloromethane (6 ml) was sonicated at 25 ° C. for 30 minutes and then o-nitrobenzyl. Bromide (1.72 g, 0.8 mmol) and n-BuN ⁺ I ⁻ (589 mg, 1.59 mmol) were added, and the mixture was further stirred at room temperature under an argon atmosphere for 24 hours. The reaction mixture was diluted with 5 ml of water and extracted with dichloromethane. The extract was washed with brine and concentrated to give 2.17 g of a pale yellow oil. This was purified by column chromatography using chloroform to obtain the title compound (16t, 585 mg, 88%) as a pale yellow oily substance.

(Example 24)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (m-nitrobenzyl) -D-erythritol compound (16u) (Scheme 4)
Compound (14) (500 mg, 1.77 mmol) was m-nitrobenzylated in substantially the same manner as the synthesis of compound (16t) to give the title compound (16u, 640 mg, 87%) as a pale yellow oil. It was.

(Example 25)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (p-nitrobenzyl) -D-erythritol compound (16v) (Scheme 4)
In substantially the same manner as the synthesis of compound (16t), compound (14) (300 mg, 1.06 mmol) was p-nitrobenzylated to give the title compound (16v, 386 mg, 87%) as a pale yellow oil. It was.

(Example 26)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (p- (p-methoxybenzyloxymethyl) benzyl) -D-erythritol compound (16w) (Scheme 4)
Compound (14) (300 mg, 1.06 mmol) was benzylated in substantially the same manner as the synthesis of compound (16t) to give the title compound (16w, 521 mg, 94%) as a colorless oil.

(Example 27)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (naphthaleyl-1-yl) methyl) -D-erythritol compound (16x) (Scheme 4)
In substantially the same manner as the synthesis of Compound (16a), Compound (14) (200 mg, 0.71 mmol) was naphthalated 1-ylmethylated to give the title compound (16x, 291 mg, 97%) as a colorless oil. .

(Example 28)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (naphthalene-2-yl) methyl) -D-erythritol compound (16y) (Scheme 4)
In substantially the same manner as the synthesis of compound (16a), compound (14) (200 mg, 0.71 mmol) was naphthalated-2-ylmethylated to give the title compound (16x, 275 mg, 92%) as a colorless oil. .

(Example 29)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (pyridin-3-ylmethyl) -D-erythritol compound (16z) (Scheme 4)
Compound (14) (500 mg, 1.77 mmol) was pyridin-3-ylmethylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16x, 615 mg, 93%) as a colorless oil. It was.

(Example 30)
3,4-O-isopropylidene-1-O- (p-methoxybenzyl) -2-O- (pyridin-4-ylmethyl) -D-erythritol compound (16aa) (Scheme 4)
Compound (14) (400 mg, 1.42 mmol) was pyridin-4-ylmethylated in substantially the same manner as the synthesis of compound (16a) to give the title compound (16aa, 500 mg, 95%) as a colorless oil. It was.

(Example 31)
1-O-benzyl-2-O-methyl-D-erythritol compound (17a) (Scheme 4)
A mixture of compound (16a, 2.0 g, 7.5 mmol), 1 ml hydrochloric acid 4 ml and ethanol 6 ml was heated under reflux for 30 minutes. After removing the solvent, the residue was dissolved in 20 ml of ethanol, and the resulting mixture was neutralized with an ion exchange resin (IRA67). After removing the ion exchange resin by filtration, the filtrate was concentrated to obtain 2.0 g of a pale yellow oily substance. When this oily substance was ground with n-hexane, almost pure compound (17a) was obtained as a colorless oily substance. This material was used in the next step without further purification.

(Example 32)
1-O-benzyl-2-O-ethyl-D-erythritol compound (17b) (Scheme 4)
Hydrolysis of compound (16b) (2.1 g, 8.1 mmol) with 1% hydrochloric acid in a manner substantially similar to the synthesis of compound (17a) yields almost pure title compound (17b) quantitatively. It was. This material was used in the next step without further purification.

(Example 33)
1-O-benzyl-2-O- (1-pentyl) -D-erythritol compound (17c) (Scheme 4)
Compound (16c) (798 mg, 2.5 mmol) was hydrolyzed with 1% hydrochloric acid by a method substantially similar to the synthesis of compound (17a). After cooling, the reaction mixture was diluted with water and the resulting mixture was neutralized with sodium bicarbonate and extracted with diethyl ether. The extract was washed with brine and then concentrated under reduced pressure to quantitatively obtain the almost pure title compound (17c) as a colorless oil. This material was used in the next step without further purification.

(Example 34)
1-O-benzyl-2-O- (1-heptyl) -D-erythritol compound (17d) (Scheme 4)
Hydrolysis of compound (16d) (637 mg, 1.82 mmol) with 1% hydrochloric acid in substantially the same manner as the synthesis of compound (17a) yielded almost pure title compound (17d) as a colorless oil quantitatively. Obtained. This material was used in the next step without further purification.

(Example 35)
1-O-benzyl-2-O- (1-tridecyl) -D-erythritol compound (17e) (Scheme 4)
Hydrolysis of compound (16e) (1.15 g, 2.65 mmol) with 1% hydrochloric acid in substantially the same manner as the synthesis of compound (17a) quantified almost pure title compound (17e) as a colorless oil. Obtained. This material was used in the next step without further purification.

(Example 36)
1-O-benzyl-2-O-neopentyl-D-erythritol compound (17f) (Scheme 4)
Hydrolysis of compound (16f) (161 mg, 0.5 mmol) with 0.5 ml of 1% hydrochloric acid in substantially the same manner as the synthesis of compound (17a) gave almost pure title compound (17f) as a colorless oil. Obtained quantitatively. This material was used in the next step without further purification.

(Example 37)
2-O-benzyl-1-O- (o-methoxybenzyl) -D-erythritol compound (17 g) (Scheme 4)
Compound (16 g) (360 mg, 0.97 mmol) was hydrolyzed for 7 hours at room temperature in a mixture of 3.0 ml acetic acid and 1.5 ml water. The resulting reaction mixture was diluted with 50 ml of water, neutralized with sodium bicarbonate, and extracted with diethyl ether. The extract was washed with brine and concentrated under reduced pressure to quantitatively obtain the almost pure title compound (17 g) as a colorless oil. This material was used in the next step without further purification.

(Example 38)
2-O- (o-methylbenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (17h) (Scheme 4)
Hydrolysis of compound (16h) (160 mg, 0.41 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17 g) yielded almost pure title compound (17h) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 39)
2-O- (m-methylbenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (17i) (Scheme 4)
Hydrolysis of compound (16i) (200 mg, 0.52 mmol) with aqueous acetic acid in a manner substantially similar to the synthesis of compound (17 g) yielded almost pure title compound (17i) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 40)
2-O- (p-methylbenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (17j) (Scheme 4)
Hydrolysis of compound (16j) (190 mg, 0.49 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17 g) yielded almost pure title compound (17j) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 41)
2-O- (o-chlorobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (17k) (Scheme 4)
Hydrolysis of compound (16k) (144 mg, 0.35 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17 g) yielded almost pure title compound (17k) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 42)
2-O- (m-chlorobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (171) (Scheme 4)
Hydrolysis of compound (16l) (470 mg, 1.16 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17 g) yielded almost pure title compound (17l) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 43)
2-O- (p-chlorobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (17m) (Scheme 4)
Hydrolysis of compound (16m) (277 mg, 0.681 mmol) with aqueous acetic acid in a manner substantially analogous to the synthesis of compound (17 g) yielded almost pure title compound (17m) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 44)
2-O- (o-bromobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (17n) (Scheme 4)
Hydrolysis of compound (16n) (404 mg, 0.90 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17 g) yielded almost pure title compound (17n) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 45)
2-O- (m-bromobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (17o) (Scheme 4)
Hydrolysis of compound (16o) (422 mg, 0.94 mmol) with aqueous acetic acid in a manner substantially analogous to the synthesis of compound (17g) yielded almost pure title compound (17o) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 46)
2-O- (p-bromobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (17p) (Scheme 4)
Hydrolysis of compound (16p) (485 mg, 1.08 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17 g) yielded almost pure title compound (17p) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 47)
1-O- (p-methoxybenzyl) -2-O- (o-trifluoromethylbenzyl) -D-erythritol compound (17q) (Scheme 4)
Hydrolysis of compound (16q) (531 mg, 1.21 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17g) yielded almost pure title compound (17q) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 48)
1-O- (p-methoxybenzyl) -2-O- (m-trifluoromethylbenzyl) -D-erythritol compound (17r) (Scheme 4)
Hydrolysis of compound (16r) (302 mg, 0.69 mmol) with aqueous acetic acid in a manner substantially similar to the synthesis of compound (17 g) yielded almost pure title compound (17r) as a colorless oil quantitatively. It was. This material was used in the next step without further purification.

(Example 49)
1-O- (p-methoxybenzyl) -2-O- (p-trifluoromethylbenzyl) -D-erythritol compound (17s) (Scheme 4)
Hydrolysis of compound (16p) (280 mg, 0.64 mmol) with aqueous acetic acid in a manner substantially similar to the synthesis of compound (17 g) yielded almost pure title compound (17s) as a colorless solid quantitatively. It was. This material was used in the next step without further purification.

(Example 50)
1-O- (p-methoxybenzyl) -2-O- (o-nitrobenzyl) -D-erythritol compound (17t) (Scheme 4)
Hydrolysis of compound (16t) (572 mg, 1.37 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17 g) yielded almost pure title compound (17t) as a pale yellow oil. Obtained. This material was used in the next step without further purification.

(Example 51)
1-O- (p-methoxybenzyl) -2-O- (m-nitrobenzyl) -D-erythritol compound (17u) (Scheme 4)
Hydrolysis of compound (16u) (620 mg, 1.48 mmol) with aqueous acetic acid in a manner substantially similar to the synthesis of compound (17 g) yielded almost pure title compound (17u) as a pale yellow oil. Obtained. This material was used in the next step without further purification.

(Example 52)
1-O- (p-methoxybenzyl) -2-O- (p-nitrobenzyl) -D-erythritol compound (17v) (Scheme 4)
Hydrolysis of compound (16v) (252 mg, 0.60 mmol) with aqueous acetic acid in a manner substantially similar to the synthesis of compound (17g) yielded almost pure title compound (17v) as a colorless solid quantitatively. It was. This material was used in the next step without further purification.

(Example 53)
1-O- (p-methoxybenzyl) -2-O- (p- (p-methoxybenzyloxymethyl) benzyl) -D-erythritol compound (17w) (Scheme 4)
Hydrolysis of compound (16w) (496 mg, 0.95 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17g) yielded almost pure title compound (17w) as a pale yellow oil. Obtained. This material was used in the next step without further purification.

(Example 54)
1-O- (p-methoxybenzyl) -2-O- (naphthalen-1-ylmethyl) -D-erythritol compound (17x) (Scheme 4)
Hydrolysis of compound (16x) (257 mg, 0.61 mmol) with aqueous acetic acid in a manner substantially similar to the synthesis of compound (17 g) yielded almost pure title compound (17x) as a colorless solid quantitatively. It was. This material was used in the next step without further purification.

(Example 55)
1-O- (p-methoxybenzyl) -2-O- (naphthalen-2-ylmethyl) -D-erythritol compound (17y) (Scheme 4)
Hydrolysis of compound (16y) (270 mg, 0.63 mmol) with aqueous acetic acid in a manner substantially similar to the synthesis of compound (17 g) yielded almost pure title compound (17y) as a colorless solid quantitatively. It was. This material was used in the next step without further purification.

(Example 56)
1-O- (p-methoxybenzyl) -2-O- (pyridin-3-ylmethyl) -D-erythritol compound (17z) (Scheme 4)
Hydrolysis of compound (16z) (517 mg, 1.38 mmol) with aqueous acetic acid in a manner substantially analogous to the synthesis of compound (17 g) yielded almost pure title compound (17z) as a pale yellow oil. Obtained. This material was used in the next step without further purification.

(Example 57)
1-O- (p-methoxybenzyl) -2-O- (pyridin-4-ylmethyl) -D-erythritol compound (17aa) (Scheme 4)
Hydrolysis of compound (16aa) (482 mg, 1.29 mmol) with aqueous acetic acid in substantially the same manner as the synthesis of compound (17 g) yielded almost pure title compound (17aa) as a pale yellow oil. Obtained. This material was used in the next step without further purification.

(Example 58)
3,4-Anhydro-1-O-benzyl-2-O-methyl-D-erythritol compound (18a) (Scheme 4)
To a mixture of the compound (17a, 1.51 g, 6.7 mmol), triphenylphosphine (TPP, 2.1 g, 8.0 mmol) and 10 ml of toluene, diethyl azodicarboxylate (EDAD) in toluene (3.9 ml, 8. 6 mmol) 40% solution was added dropwise at 80 ° C. The resulting reaction mixture was stirred at room temperature for 30 minutes and heated at reflux for an additional 4 hours. After removal of the solvent, the residue is triturated in diethyl ether: n-hexane (1: 1) solution, the precipitated solid is filtered off and the filtrate is concentrated to give an orange oil (2.61 g). It was. This was purified by column chromatography (hexane-AcOEt; 20: 1 → 10: 1) to give the title compound (18a) (1.07 g, 77%) as a colorless oil.

(Example 59)
3,4-Anhydro-1-O-benzyl-2-O-ethyl-D-erythritol compound (18b) (Scheme 4)
Epoxidation of compound (17b) (1.36 g, 5.7 mmol) with TPP and DEAD in substantially the same manner as the synthesis of compound (18a) gave the title compound (18b, 956 mg, 76%). Obtained as a colorless oil.

(Example 60)
3,4-Anhydro-1-O-benzyl-2-O- (1-pentyl) -D-erythritol compound (18c) (Scheme 4)
Epoxidation of compound (17c) (600 mg, 2.12 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18c, 460 mg, 82%) as a colorless oil It was obtained as a product.

(Example 61)
3,4-Anhydro-1-O-benzyl-2-O- (1-heptyl) -D-erythritol compound (18d) (Scheme 4)
Epoxidation of compound (17d) (544 mg, 1.75 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18d, 435 mg, 85%) as a colorless oil It was obtained as a product.

(Example 62)
3,4-Anhydro-1-O-benzyl-2-O- (1-tridecyl) -D-erythritol compound (18e) (Scheme 4)
Epoxidation of compound (17e) (1.0 g, 2.5 mmol) using TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) yields the title compound (18e, 772 mg, 81%). Obtained as a colorless oil.

(Example 63)
3,4-Anhydro-1-O-benzyl-2-O-neopentyl-D-erythritol compound (18f) (Scheme 4)
Epoxidation of compound (17f) (110 mg, 0.39 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18f, 91 mg, 89%) as a colorless oil It was obtained as a product.

(Example 64)
3,4-Anhydro-2-O-benzyl-1-O- (p-methoxybenzyl) -D-erythritol compound (18 g) (Scheme 4)
Epoxidation of compound (17 g) (200 mg, 0.6 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18 g, 210 mg, 90%) as a colorless oil It was obtained as a product.

(Example 65)
3,4-Anhydro-2-O- (o-methylbenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (18h) (Scheme 4)
Epoxidation of compound (17h) (125 mg, 0.36 mmol) using TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18h, 93 mg, 79%) as a colorless oil It was obtained as a product.

Example 66
3,4-Anhydro-2-O- (m-methylbenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (18i) (Scheme 4)
Epoxidation of compound (17i) (150 mg, 0.433 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18i, 119 mg, 84%) as a colorless oil It was obtained as a product.

(Example 67)
3,4-Anhydro-2-O- (p-methylbenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (18j) (Scheme 4)
Epoxidation of compound (17h) (150 mg, 0.43 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18j, 108 mg, 76%) as a colorless oil It was obtained as a product.

Example 68
3,4-Anhydro-2-O- (o-chlorobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (18k) (Scheme 4)
Epoxidation of compound (17k) (120 mg, 0.33 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18k, 86 mg, 75%) as a colorless oil It was obtained as a product.

(Example 69)
3,4-Anhydro-2-O- (m-chlorobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (181) (Scheme 4)
Epoxidation of compound (17l) (200 mg, 0.55 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18l, 146 mg, 77%) as a colorless oil It was obtained as a product.

(Example 70)
3,4-Anhydro-2-O- (p-chlorobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (18m) (Scheme 4)
Epoxidation of compound (17m) (170 mg, 0.46 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18m, 139 mg, 86%) as a colorless oil It was obtained as a product.

(Example 71)
3,4-Anhydro-2-O- (o-bromobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (18n) (Scheme 4)
Epoxidation of compound (17n) (349 mg, 0.85 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18n, 287 mg, 86%) as a colorless oil It was obtained as a product.

(Example 72)
3,4-Anhydro-2-O- (m-bromobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (18o) (Scheme 4)
Epoxidation of compound (17o) (337 mg, 0.82 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18o, 285 mg, 85%) as a colorless oil It was obtained as a product.

(Example 73)
3,4-Anhydro-2-O- (p-bromobenzyl) -1-O- (p-methoxybenzyl) -D-erythritol compound (18p) (Scheme 4)
Epoxidation of compound (17p) (361 mg, 0.88 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18p, 283 mg, 82%) as a colorless oil It was obtained as a product.

(Example 74)
3,4-Anhydro-2-O- (p-methoxybenzyl) -1-O- (o-trifluoromethylbenzyl) -D-erythritol compound (18q) (Scheme 4)
Epoxidation of compound (17q) (482 mg, 1.21 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18q, 405 mg, 88%) as a colorless oil It was obtained as a product.

(Example 75)
3,4-Anhydro-2-O- (p-methoxybenzyl) -1-O- (m-trifluoromethylbenzyl) -D-erythritol compound (18r) (Scheme 4)
Epoxidation of compound (17r) (268 mg, 0.67 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18r, 202 mg, 79%) as a colorless oil It was obtained as a product.

(Example 76)
3,4-Anhydro-2-O- (p-methoxybenzyl) -1-O- (p-trifluoromethylbenzyl) -D-erythritol compound (18s) (Scheme 4)
Epoxidation of compound (17s) (250 mg, 0.65 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18s, 191 mg, 80%) as a colorless oil It was obtained as a product.

(Example 77)
3,4-Anhydro-2-O- (p-methoxybenzyl) -1-O- (o-nitrobenzyl) -D-erythritol compound (18t) (Scheme 4)
Epoxidation of compound (17t) (510 mg, 1.35 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18t, 408 mg, 84%) as a colorless oil It was obtained as a product.

(Example 78)
3,4-Anhydro-2-O- (p-methoxybenzyl) -1-O- (m-nitrobenzyl) -D-erythritol compound (18u) (Scheme 4)
Epoxidation of compound (17m) (545 mg, 1.44 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18u, 424 mg, 82%) as a colorless oil It was obtained as a product.

(Example 79)
3,4-Anhydro-2-O- (p-methoxybenzyl) -1-O- (p-nitrobenzyl) -D-erythritol compound (18v) (Scheme 4)
Epoxidation of compound (17v) (230 mg, 0.61 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18v, 184 mg, 85%) as a colorless oil It was obtained as a product.

(Example 80)
3,4-Anhydro-1-O- (p-hydroxymethylbenzyl) -2-O- (p- (p-methoxybenzyloxymethyl) benzyl) -D-erythritol compound (18w) (Scheme 4)
Epoxidation of compound (17w) (450 mg, 0.93 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18w, 323 mg, 75%) as a colorless oil It was obtained as a product.

(Example 81)
3,4-Anhydro-1-O- (p-methoxybenzyl) -2-O- (naphthalen-1-ylmethyl) -D-erythritol compound (18x) (Scheme 4)
Epoxidation of compound (17x) (185 mg, 0.48 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18x, 140 mg, 80%) as a colorless oil It was obtained as a product.

(Example 82)
3,4-Anhydro-1-O- (p-methoxybenzyl) -2-O- (naphthalen-2-ylmethyl) -D-erythritol compound (18y) (Scheme 4)
Epoxidation of compound (17y) (220 mg, 0.57 mmol) using TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18y, 157 mg, 75%) as a colorless oil It was obtained as a product.

(Example 83)
3,4-Anhydro-1-O- (p-methoxybenzyl) -2-O- (pyridin-3-ylmethyl) -D-erythritol compound (18z) (Scheme 4)
Epoxidation of compound (17z) (395 mg, 1.18 mmol) with TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18z, 214 mg, 52%) as a pale yellow color Obtained as an oil.

(Example 84)
3,4-Anhydro-1-O- (p-methoxybenzyl) -2-O- (pyridin-4-ylmethyl) -D-erythritol compound (18z) (Scheme 4)
Epoxidation of compound (17aa) (420 mg, 1.26 mmol) using TPP and DEAD in a manner substantially analogous to the synthesis of compound (18a) gave the title compound (18aa, 204 mg, 51%) as a colorless oil It was obtained as a product.

(Example 85)
2,3,5-Tri-O-benzyl-1,4-[(R)-[1-O-benzyl-4-deoxy-2-O-methyl-D-erythritol-4-yl] episulfonium Den] -1,4-dideoxy-D-arabitol chloride (20a, X = Cl) (Scheme 5)
To a mixture of epoxide compound (18a, 100 mg, 0.48 mmol), thiosugar compound (19a) (168 mg, 0.4 mmol) and dichloromethane 2 ml, tetrafluoroboric acid dimethyl ether complex (HBF _4. (CH ₃ ) ₂ O, 63 μl , 0.52 mmol) was added at -60 ° C. The reaction mixture was stirred for 3 hours and concentrated under reduced pressure. The residue in methanol 3 ml, at room temperature ion-exchange resin IRA-400 J ^- was treated with (Cl type), The resin was removed by filtration and the filtrate concentrated to give an oil (290 mg). This was purified by column chromatography (chloroform → chloroform / methanol, 100: 1 → 50: 1) to obtain the title compound (20a, 234 mg, 88%).

(Example 86)
2,3,5-tri-O-benzyl-1,4-[(R)-[1-O-benzyl-4-deoxy-2-O-ethyl-D-erythritol-4-yl] episulfonium Den] -1,4-dideoxy-D-arabitol chloride (20b, X = Cl) (Scheme 5)
A coupling reaction between the epoxide compound (18b) and the thiosaccharide (19a, 158 mg, 0.38 mmol) was carried out by a method substantially similar to the synthesis of the compound (20a), followed by an ion exchange reaction. 20b, 204 mg, 80%) was obtained as a colorless oil.

(Example 87)
2,3,5-tri-O-benzyl-1,4-[(R)-[1-O-benzyl-4-deoxy-2-O- (1-pentyl) -D-erythritol-4-yl] Episulfonyl mylidene] -1,4-dideoxy-D-arabitol chloride (20c, X = Cl) (Scheme 5)
The epoxide compound (18c, 150 mg, 0.57 mmol) and the thiosaccharide (19a, 200 mg, 0.48 mmol) were coupled with each other by a method substantially similar to the synthesis of the compound (20a), and then the ion exchange reaction was When done, the title compound (20c, 281 mg, 82%) was obtained as a colorless oil.

(Example 88)
2,3,5-tri-O-benzyl-1,4-[(R)-[1-O-benzyl-4-deoxy-2-O- (1-heptyl) -D-erythritol-4-yl] Episulfonyl mylidene] -1,4-dideoxy-D-arabitol chloride (20d, X = Cl) (Scheme 5)
The epoxide compound (18d, 130 mg, 0.45 mmol) and the thiosaccharide (19a, 156 mg, 0.37 mmol) were coupled with each other by a method substantially similar to the synthesis of the compound (20a), and then the ion exchange reaction was When done, the title compound (20d, 231 mg, 83%) was obtained as a colorless oil.

Example 89
2,3,5-tri-O-benzyl-1,4-[(R)-[1-O-benzyl-4-deoxy-2-O- (1-tridecyl) -D-erythritol-4-yl] Episulfonyl mylidene] -1,4-dideoxy-D-arabitol chloride (20e, X = Cl) (Scheme 5)
The epoxide compound (18e, 100 mg, 0.27 mmol) and the thiosaccharide (19a, 93 mg, 0.22 mmol) were coupled with each other by a method substantially similar to the synthesis of the compound (20a), and then the ion exchange reaction was performed. When done, the title compound (20e, 154 mg, 81%) was obtained as a colorless oil.

(Example 90)
2,3,5-Tri-O-benzyl-1,4-[(R)-[1-O-benzyl-4-deoxy-2-O-neopentyl-D-erythritol-4-yl] episulfonium Den] -1,4-dideoxy-D-arabitol chloride (20f, X = Cl) (Scheme 5)
The epoxide compound (18f, 60 mg, 0.23 mmol) and the thiosaccharide (19a, 69 mg, 0.16 mmol) were coupled with each other by a method substantially similar to the synthesis of the compound (20a), and then an ion exchange reaction was performed. When done, the title compound (20f, 98 mg, 83%) was obtained as a colorless oil.

(Example 91)
1,4-[(R)-[2-O-benzyl-4-deoxy-1-O- (p-methoxybenzyl) -D-erythritol-4-yl] episulfonium myridene] -1,4- Dideoxy-2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20 g, X = BF ₄ ) (Scheme 5)
To a mixture of epoxide compound (18 g, 100 mg, 0.32 mmol), thiosugar (19b, 136 mg, 0.27 mmol) and dichloromethane 2 ml, tetrafluoroboric acid dimethyl ether complex (HBF _4. (CH ₃ ) ₂ O, 63 μl) , 0.52 mmol) was added at -60 ° C. The resulting reaction mixture was stirred at −60 ° C. for 3 hours. After the reaction was quenched by adding sodium acetate at −60 ° C., the resulting suspension was filtered and the resulting inorganic material was washed with dichloromethane. The filtrate and the washed product were combined and concentrated under reduced pressure to obtain 284 mg of a pale yellow oil. . The residue in methanol (3 mL), ion-exchange resin IRA-400 J at room temperature ^- was treated with (Cl type). This was purified by column chromatography (chloroform → chloroform / methanol, 50: 1 → 10: 1)) to give the title compound (20 g, 185 mg, 76%) as a colorless oil.

(Example 92)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (o-methylbenzyl) -D-erythritol-4-yl] Episulfonyl mylidene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20 h, X = BF ₄ ) (Scheme 5)
In substantially the same manner as the synthesis of compound (20 g), epoxide compound (18h, 33 mg, 0.24 mmol) and thiosaccharide (19b, 102 mg, 0.20 mmol) were combined with tetrafluoroboric acid dimethyl ether complex (33 μl, 0 .27 mmol) and purified by column chromatography to give the title compound (20h, 96 mg, 52%) as a colorless oil.

(Example 93)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (m-methylbenzyl) -D-erythritol-4-yl] Episulfonyl mylidene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20i, X = BF ₄ ) (Scheme 5)
The epoxide compound (18i, 77 mg, 0.24 mmol) and the thiosaccharide (19b, 100 mg, 0.20 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (33 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .27 mmol) and purified by column chromatography to give the title compound (20i, 94 mg, 52%) as a colorless oil.

(Example 94)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (p-methylbenzyl) -D-erythritol-4-yl] Episulfonyl mylidene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20j, X = BF ₄ ) (Scheme 5)
The epoxide compound (18j, 72 mg, 0.22 mmol) and the thiosugar (19b, 94 mg, 0.18 mmol) were converted into a tetrafluoroboric acid dimethyl ether complex (30 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .25 mmol) and purified by column chromatography to give the title compound (20j, 85 mg, 50%) as a colorless oil.

(Example 95)
1,4-[(R)-[2-O- (o-chlorobenzyl) -4-deoxy-1-O- (p-methoxybenzyl) -D-erythritol-4-yl] episulfonium myridene] -1,4-dideoxy-2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20k, X = BF ₄ ) (Scheme 5)
The epoxide compound (18k, 69 mg, 0.20 mmol) and the thiosugar (19b, 84 mg, 0.16 mmol) were converted into a tetrafluoroboric acid dimethyl ether complex (27 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .22 mmol) and purified by column chromatography to give the title compound (20k, 76 mg, 49%) as a colorless oil.

(Example 96)
1,4-[(R)-[2-O- (m-chlorobenzyl) -4-deoxy-1-O- (p-methoxybenzyl) -D-erythritol-4-yl] episulfonium myridene] -1,4-dideoxy-2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20 l, X = BF ₄ ) (Scheme 5)
In substantially the same manner as the synthesis of the compound (20 g), an epoxide compound (181, 82 mg, 0.24 mmol) and a thiosaccharide (19b, 100 mg, 0.20 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (27 μl, 0 .22 mmol) and purified by column chromatography to give the title compound (20 l, 103 mg, 56%) as a colorless oil.

(Example 97)
1,4-[(R)-[2-O- (p-chlorobenzyl) -4-deoxy-1-O- (p-methoxybenzyl) -D-erythritol-4-yl] episulfonium myridene] -1,4-dideoxy-2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20 m, X = BF ₄ ) (Scheme 5)
In substantially the same manner as the synthesis of the compound (20 g), an epoxide compound (18 m, 69 mg, 0.20 mmol) and a thiosugar (19b, 84 mg, 0.16 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (27 μl, 0 .22 mmol) and purified by column chromatography to give the title compound (20 m, 68 mg, 44%) as a colorless oil.

(Example 98)
1,4-[(R)-[2-O- (o-bromobenzyl) -4-deoxy-1-O- (p-methoxybenzyl) -D-erythritol-4-yl] episulfonium myridene] -1,4-dideoxy-2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20 n, X = BF ₄ ) (Scheme 5)
In substantially the same manner as the synthesis of the compound (20 g), an epoxide compound (18n, 102 mg, 0.28 mmol) and a thiosugar (19b, 112 mg, 0.22 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (39 μl, 0 .28 mmol) and purified by column chromatography to give the title compound (20n, 89 mg, 41%) as a colorless oil.

Example 99
1,4-[(R)-[2-O- (m-bromobenzyl) -4-deoxy-1-O- (p-methoxybenzyl) -D-erythritol-4-yl] episulfonium myridene] -1,4-dideoxy-2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20o, X = BF ₄ ) (Scheme 5)
The epoxide compound (18o, 102 mg, 0.26 mmol) and the thiosugar (19b, 110 mg, 0.21 mmol) were converted into a tetrafluoroboric acid dimethyl ether complex (39 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .28 mmol) and purified by column chromatography to give the title compound (20o, 85 mg, 40%) as a colorless oil.

(Example 100)
1,4-[(R)-[2-O- (p-bromobenzyl) -4-deoxy-1-O- (p-methoxybenzyl) -D-erythritol-4-yl] episulfonium myridene] -1,4-dideoxy-2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20p, X = BF ₄ ) (Scheme 5)
The epoxide compound (18p, 106 mg, 0.27 mmol) and the thiosugar (19b, 115 mg, 0.23 mmol) were converted into a tetrafluoroboric acid dimethyl ether complex (41 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .29 mmol) and purified by column chromatography to give the title compound (20p, 98 mg, 46%) as a colorless oil.

(Example 101)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (o-trifluoromethylbenzyl) -D-erythritol-4- Yl] episulfonirimidene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20q, X = BF ₄ ) (Scheme 5)
The epoxide compound (18q, 101 mg, 0.26 mmol) and the thiosugar (19b, 111 mg, 0.22 mmol) were converted into a tetrafluoroboric acid dimethyl ether complex (39 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .28 mmol) and purified by column chromatography to give the title compound (20q, 120 mg, 56%) as a colorless oil.

(Example 102)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (m-trifluoromethylbenzyl) -D-erythritol-4- Yl] episulfonylmylidene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20r, X = BF ₄ ) (Scheme 5)
The epoxide compound (18r, 129 mg, 0.34 mmol) and the thiosugar (19b, 144 mg, 0.28 mmol) were converted into a tetrafluoroboric acid dimethyl ether complex (50 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .37 mmol) and purified by column chromatography to give the title compound (20r, 134 mg, 48%) as a colorless oil.

(Example 103)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (p-trifluoromethylbenzyl) -D-erythritol-4- Yl] episulfonium myridene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20 s, X = BF ₄ ) (Scheme 5)
In substantially the same manner as the synthesis of the compound (20 g), an epoxide compound (18s, 80 mg, 0.16 mmol) and a thiosugar (19b, 92 mg, 0.18 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (31 μl, 0 .25 mmol) and purified by column chromatography to give the title compound (20s, 92 mg, 52%) as a colorless oil.

(Example 104)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (o-nitrobenzyl) -D-erythritol-4-yl] Episulfonyl mylidene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20 t, X = BF ₄ ) (Scheme 5)
In substantially the same manner as the synthesis of the compound (20 g), an epoxide compound (18t, 100 mg, 0.28 mmol) and a thiosugar (19b, 118 mg, 0.23 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (41 μl, 0 .28 mmol) and purified by column chromatography to give the title compound (20t, 110 mg, 50%) as a colorless oil.

(Example 105)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (m-nitrobenzyl) -D-erythritol-4-yl] Episulfonyl mylidene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20 u, X = BF ₄ ) (Scheme 5)
In substantially the same manner as the synthesis of compound (20 g), epoxide compound (18u, 100 mg, 0.29 mmol) and thiosugar (19b, 118 mg, 0.23 mmol) were combined with tetrafluoroboric acid dimethyl ether complex (44 μl, 0 .32 mmol) and purified by column chromatography to give the title compound (20u, 110 mg, 50%) as a colorless oil.

(Example 106)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (p-nitrobenzyl) -D-erythritol-4-yl] Episulfonyl mylidene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20v, X = BF ₄ ) (Scheme 5)
The epoxide compound (18v, 90 mg, 0.25 mmol) and the thiosugar (19b, 106 mg, 0.21 mmol) were converted into a tetrafluoroboric acid dimethyl ether complex (37 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .27 mmol) and purified by column chromatography to give the title compound (20v, 105 mg, 65%) as a colorless oil.

(Example 107)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (p- (p-methoxybenzyloxymethyl) benzyl) -D - erythritol-4-yl] episulfonium Niu millimeter Den]-2,3,5 -O- (p-methoxybenzyl)-D-arabitol tetrafluoroborate _{(20w, X = BF 4)} ( reaction Formula 5)
In substantially the same manner as the synthesis of the compound (20 g), an epoxide compound (18w, 109 mg, 0.24 mmol) and a thiosugar (19b, 100 mg, 0.31 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (42 μl, 0 .27 mmol) and purified by column chromatography to give the title compound (20w, 120 mg, 57%) as a colorless oil.

(Example 108)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (naphthalen-1-ylmethyl) -D-erythritol-4-yl ] Episulfonyl mylidene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20x, X = BF ₄ ) (Scheme 5)
In substantially the same manner as the synthesis of the compound (20 g), an epoxide compound (18x, 94 mg, 0.26 mmol) and a thiosugar (19b, 110 mg, 0.22 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (39 μl, 0 .28 mmol) and purified by column chromatography to give the title compound (20 ×, 68 mg, 33%) as a colorless oil.

(Example 109)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (naphthalen-2-ylmethyl) -D-erythritol-4-yl ] Episulfonium myridene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20y, X = BF ₄ ) (Scheme 5)
The epoxide compound (18y, 74 mg, 0.20 mmol) and the thiosugar (19b, 86 mg, 0.17 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (32 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .23 mmol) and purified by column chromatography to give the title compound (20y, 91 mg, 56%) as a colorless oil.

(Example 110)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (pyridin-3-ylmethyl) -D-erythritol-4-yl ] Episulfonium myridene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20z, X = BF ₄ ) (Scheme 5)
The epoxide compound (18z, 154 mg, 0.49 mmol) and the thiosugar (19b, 200 mg, 0.39 mmol) were converted to a tetrafluoroboric acid dimethyl ether complex (144 μl, 1) by a method substantially similar to the synthesis of the compound (20 g). .05 mmol) and purified by column chromatography to give the title compound (20z, 125 mg, 35%) as a colorless oil.

(Example 111)
1,4-dideoxy-1,4-[(R)-[4-deoxy-1-O- (p-methoxybenzyl) -2-O- (pyridin-4-ylmethyl) -D-erythritol-4-yl ] Episulfonium myridene] -2,3,5-tri-O- (p-methoxybenzyl) -D-arabitol tetrafluoroborate (20aa, X = BF ₄ ) (Scheme 5)
The epoxide compound (18aa, 100 mg, 0.32 mmol) and the thiosugar (19b, 115 mg, 0.23 mmol) were converted into a tetrafluoroboric acid dimethyl ether complex (78 μl, 0) by a method substantially similar to the synthesis of the compound (20 g). .57 mmol) and purified by column chromatography to give the title compound (20aa, 94 mg, 46%) as a colorless oil.

(Example 112)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O-methyl-D-erythritol-4-yl] episulfonylidene] -D-arabitol chloride (Ia) ( Reaction formula 5)
A 2 ml suspension of 10% palladium-carbon (100 mg) in 80% aqueous acetic acid was prereduced with hydrogen, and 3 ml of 80% aqueous acetic acid in 20% (160 mg, 0.24 mmol) of compound 20a was added to the suspension. The mixture was hydrogenated at 50-60 ° C. for 12 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give a colorless oil (78 mg). The colorless oil was observed to contaminate the partially acetylated product. The oil was treated with a mixture of 0.1 ml of 10% hydrochloric acid and 1 ml of methanol at room temperature for 3 hours, and then the solvent was removed under reduced pressure to give a colorless oil (74 mg). The resulting colorless oil was purified by column chromatography (chloroform-methanol, 10: 1 → chloroform-methanol-water, 6: 4: 1) to give the title compound (Ia) (53 mg, 72%). .

(Example 113)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O-ethyl-D-erythritol-4-yl] episulfonylidene] -D-arabitol chloride (Ib) ( Reaction formula 5)
Hydrogenation of compound (20b, 110 mg, 0.16 mmol) in a manner substantially analogous to the synthesis of compound (Ia) gave the title compound (Ib, 41 mg, 79%) as a colorless oil.

(Example 114)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (1-pentyl) -D-erythritol-4-yl] episulfonyl mylidene] -D-arabitol chloride (Ic) (Scheme 5)
Hydrogenation of compound (20c, 80 mg, 0.11 mmol) in a manner substantially analogous to the synthesis of compound (Ia) gave the title compound (Ic, 32.5 mg, 81%) as a colorless oil. .

(Example 115)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (1-heptyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride (Id) (Scheme 5)
Hydrogenation of compound (20d, 120 mg, 0.16 mmol) in a manner substantially analogous to the synthesis of compound (Ia) gave the title compound (Id, 52 mg, 83%) as a colorless oil.

(Example 116)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (1-tridecyl) -D-erythritol-4-yl] episulfonyl mylidene] -D-arabitol chloride (Ie) (Scheme 5)
Hydrogenation of compound (20e, 83 mg, 0.10 mmol) in a manner substantially analogous to the synthesis of compound (Ia) gave the title compound (Ie, 37.2 mg, 79%) as a colorless oil. .

(Example 117)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O-neopentyl-D-erythritol-4-yl] episulfonyl mylidene] -D-arabitol chloride (If) ( Reaction formula 5)
Hydrogenation of compound (20f, 60 mg, 0.08 mmol) in a manner substantially analogous to the synthesis of compound (Ia) gave the title compound (If, 24 mg, 80%) as a colorless oil.

(Example 118)
1,4-dideoxy-1,4-[(R)-[2-O-benzyl-4-deoxy-D-erythritol-4-yl] episulfonylidene] -D-arabitol chloride (Ig) ( Reaction formula 5)
The compound (20 g, 100 mg, 0.11 mmol) was treated in a mixed solution of 6 ml of 80% TFA aqueous solution and 3 ml of chloroform at room temperature for 2 hours. The obtained reaction mixture was concentrated under reduced pressure, and the residue was washed with chloroform. When 1,4-dideoxy-1,4-[(R)-[2-O-benzyl-4-deoxy-D-erythritol- 4-yl] episulfonirimidene] -D-arabitol tetrafluoroborate (Ig, X = BF ₄ ) was quantitatively obtained. This compound was stirred with ion exchange resin IRA400J (2 g) in 2 ml of methanol for 4 hours, the resin was filtered off, washed with methanol, and the filtrate and washings were combined and concentrated to give a colorless oil. The resulting colorless oil was purified by column chromatography (chloroform → chloroform-methanol 50: 1 → chloroform-methanol 10: 1) to give the title compound (Ig) (X═Cl, 34 mg, 85%) colorless. Obtained as an oil.

(Example 119)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (o-methylbenzyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Ih) (Scheme 5)
De-p-methoxybenzylation of compound (20h, 78 mg, 0.084 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Ih, 26.0 mg, 78%) as a colorless oil.

(Example 120)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (m-methylbenzyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Ii) (Scheme 5)
De-p-methoxybenzylation of compound (20i, 65 mg, 0.070 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion-exchanged. The reaction yielded the title compound (Ii, 22.4 mg, 81%) as a colorless oil.

(Example 121)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (p-methylbenzyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Ij) (Scheme 5)
De-p-methoxybenzylation of compound (20j, 65 mg, 0.070 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction gave the title compound (Ij, 21.8 mg, 78%) as a colorless oil.

(Example 122)
1,4-dideoxy-1,4-[(R)-[2-O- (o-chlorobenzyl) -4-deoxy-D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Ik) (Scheme 5)
De-p-methoxybenzylation of compound (20k, 70 mg, 0.074 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Ik, 24.3 mg, 79%) as a colorless oil.

(Example 123)
1,4-dideoxy-1,4-[(R)-[2-O- (m-chlorobenzyl) -4-deoxy-D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Il) (Scheme 5)
De-p-methoxybenzylation of compound (201, 75 mg, 0.079 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Il, 29.6 mg, 82%) as a colorless oil.

(Example 124)
1,4-dideoxy-1,4-[(R)-[2-O- (p-chlorobenzyl) -4-deoxy-D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Im) (Scheme 5)
De-p-methoxybenzylation of the compound (20 m, 60 mg, 0.063 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Im, 21.3 mg, 81%) as a colorless oil.

(Example 125)
1,4-dideoxy-1,4-[(R)-[2-O- (o-bromobenzyl) -4-deoxy-D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (In) (Scheme 5)
De-p-methoxybenzylation of compound (20n, 55 mg, 0.055 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion-exchanged. The reaction yielded the title compound (In, 19.1 mg, 83%) as a colorless oil.

(Example 126)
1,4-dideoxy-1,4-[(R)-[2-O- (m-bromobenzyl) -4-deoxy-D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Io) (Scheme 5)
De-p-methoxybenzylation of compound (20o, 53 mg, 0.053 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion-exchanged. The reaction yielded the title compound (Io, 19.2 mg, 78%) as a colorless oil.

(Example 127)
1,4-dideoxy-1,4-[(R)-[2-O- (p-bromobenzyl) -4-deoxy-D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Ip) (Scheme 5)
In substantially the same manner as the synthesis of compound (Ig), compound (20p, 65 mg, 0.06
5 mmol) was de-p-methoxybenzylated to give the corresponding sulfonium tetrafluoroborate, which was ion exchanged to give the title compound (Ip, 23.1 mg, 77%) as a colorless oil. .

(Example 128)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (o-trifluoromethylbenzyl) -D-erythritol-4-yl] episulfonium myridene] -D- Arabitol chloride (Iq) (Scheme 5)
De-p-methoxybenzylation of compound (20q, 80 mg, 0.082 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion-exchanged. The reaction yielded the title compound (Iq, 30.0 mg, 82%) as a colorless oil.

(Example 129)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (m-trifluoromethylbenzyl) -D-erythritol-4-yl] episulfonium myridene] -D- Arabitol chloride (Ir) (Scheme 5)
De-p-methoxybenzylation of compound (20r, 72 mg, 0.073 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Ir, 26.7 mg, 81%) as a colorless oil.

(Example 130)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (p-trifluoromethylbenzyl) -D-erythritol-4-yl] episulfonium myridene] -D- Arabitol chloride (Is) (Scheme 5)
De-p-methoxybenzylation of compound (20s, 90 mg, 0.092 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Is, 33.3 mg, 81%) as a colorless oil.

(Example 131)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (o-nitrobenzyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (It) (Scheme 5)
De-p-methoxybenzylation of compound (20t, 88 mg, 0.092 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (It, 31.3 mg, 80%) as a colorless oil.

(Example 132)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (m-nitrobenzyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Iu) (Scheme 5)
De-p-methoxybenzylation of compound (20u, 88 mg, 0.092 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Iu, 18.7 mg, 81%) as a colorless oil.

(Example 133)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (p-nitrobenzyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol chloride Compound (Iv) (Scheme 5)
De-p-methoxybenzylation of compound (20v, 95 mg, 0.099 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Iv, 34.6 mg, 82%) as a colorless oil.

(Example 134)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (p-hydroxymethyl) benzyl) -D-erythritol-4-yl] episulfonium myridene] -D- Arabitol chloride (Iw) (Scheme 5)
De-p-methoxybenzylation of compound (20w, 101 mg, 0.095 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Iw, 30.4 mg, 78%) as a colorless oil.

(Example 135)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (naphthalen-1-ylmethyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol Chloride (Ix) (Scheme 5)
De-p-methoxybenzylation of compound (20x, 64 mg, 0.066 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Ix, 22.0 mg, 77%) as a colorless oil.

(Example 136)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (naphthalen-2-ylmethyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol Chloride (Iy) (Scheme 5)
De-p-methoxybenzylation of compound (20y, 56 mg, 0.058 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion-exchanged. The reaction yielded the title compound (Iy, 19.1 mg, 76%) as a colorless oil.

(Example 137)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (pyridin-3-ylmethyl) -D-erythritol-4-yl] episulfonium myridene] -D-arabitol Chloride (Iz) (Scheme 5)
De-p-methoxybenzylation of compound (20z, 98 mg, 0.107 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Iz, 37.0 mg, 82%) as a colorless oil.

(Example 138)
1,4-dideoxy-1,4-[(R)-[4-deoxy-2-O- (pyridin-4-ylmethyl) -D-erythritol-4-yl] episulfonyl mylidene] -D-arabitol Chloride (Iaa) (Scheme 5)
De-p-methoxybenzylation of compound (20aa, 90 mg, 0.098 mmol) in a manner substantially similar to the synthesis of compound (Ig) provides the corresponding sulfonium tetrafluoroborate, which is ion exchanged. The reaction yielded the title compound (Iaa, 33.2 mg, 81%) as a colorless oil.

(Example 139)
Rat small intestinal brush border membrane vesicles were prepared (Kessler, M. et. Al., Biochim. Biophys. Acta., 1978, 506, 136) in 0.1M maleate buffer (pH 6.0). Were used as small intestinal α-glucosidases (maltase, sucrase, and isomaltase).

The test compound was dissolved in dimethyl sulfoxide (DMSO), and the resulting solution was diluted with 0.1 M maleate buffer to prepare a test compound solution (DMSO concentration: 10%). A substrate solution (sucrose (74 mM), maltose (74 mM) or isomaltose (74 mM), 50 μL), a test compound solution (25 μL), and an enzyme solution (25 μL) in a maleate buffer solution were mixed. Incubate for 30 minutes at ° C. After incubation, the solution was immediately heated with boiling water to stop the reaction and mixed with water (150 μL). The glucose concentration was measured by the glucose oxidase method. The final concentration of DMSO in the test solution was 2.5%, and no influence of DMSO on the inhibitory activity was detected. A 50% inhibitory concentration (IC ₅₀ ) was calculated from the obtained value.

As is apparent from the results in Table 1, compound (Ia) -d, which is within the scope of the present invention, exhibits an excellent glucosidase inhibitory effect.

Since the novel cyclic sulfonium salt compound of the present invention or its isomer, solvate or pharmaceutically acceptable salt thereof has α-glucosidase inhibitory activity, it is used as a prophylactic or therapeutic agent for diabetes or health food. It is also useful and industrially has high utility value.

Claims (9)

Formula (I):

[Where:
R ¹ represents a hydrogen atom or — (CH (OH)) _n —CH ₂ OH (n is an integer of 0 to 2);
R ² is
(I) unsubstituted or substituted _C 1 _{-C 16} alkyl group (where, n excluding methyl group when the 1),
(Ii) unsubstituted or substituted C ₃ -C ₆ cycloalkyl,
(Iii) General formula (Ia): represented by —R ₁ —R ₂ (wherein R ₁ represents a C ₁ -C ₄ alkylene group and R ₂ represents a monovalent aromatic cyclic group). An unsubstituted or substituted aralkyl group, or (iv) general formula (Ia): —R ₃ —R ₄ (wherein R ₃ represents a C ₁ -C ₄ alkylene group, and R ₄ represents a monovalent heterocyclic ring) A hydrophobic group consisting of an unsubstituted or substituted heteroaralkyl group represented by the formula group; and
X ⁻ means a conjugate base ion of Bronsted acid]
Or a stereoisomer , solvate or pharmaceutically acceptable salt thereof. General formula (II):

(Wherein R ¹ represents — (CH (OH)) _n —CH ₂ OH (n is an integer of 0 to 3);
R ² is
(I) unsubstituted or substituted _C 1 _{-C 16} alkyl group (where, n excluding methyl group when the 1),
(Ii) unsubstituted or substituted C ₃ -C ₆ cycloalkyl,
(Iii) General formula (Ia): represented by —R ₁ —R ₂ (wherein R ₁ represents a C ₁ -C ₄ alkylene group and R ₂ represents a monovalent aromatic cyclic group). An unsubstituted or substituted aralkyl group, or (iv) general formula (Ia): —R ₃ —R ₄ (wherein R ₃ represents a C ₁ -C ₄ alkylene group, and R ₄ represents a monovalent heterocyclic ring) A hydrophobic group consisting of an unsubstituted or substituted heteroaralkyl group represented by the formula group; and
X ⁻ means a conjugate base ion of Bronsted acid]
Or a stereoisomer , solvate or pharmaceutically acceptable salt thereof. The cyclic sulfonium salt compound according to any one of claims 1 to 2, or a stereoisomer , solvate or pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or -CH ₂ OH. Or a cyclic sulfonium salt compound consisting of-(CH ₂ ) ₂ -CH ₂ OH, or a stereoisomer , solvate or pharmaceutically acceptable salt thereof. The cyclic sulfonium salt compound according to any one of claims 1 to 2, or a stereoisomer , solvate, or pharmaceutically acceptable salt thereof, wherein R ² is a C ₁ -C ₁₃ alkyl. Group, or benzyl group, o-, m- or p-halobenzyl group, o-, m- or p-nitrobenzyl group, o-, m- or p-methylbenzyl group, o-, m- or p-tri A cyclic sulfonium salt compound consisting of a fluoromethylbenzyl group, a hydroxymethylbenzyl group, a naphthylmethyl group or a pyridylmethyl group, or a stereoisomer , solvate or pharmaceutically acceptable salt thereof. Cyclic sulfonium salt compound or a stereoisomer of any one of claims 1 to 2, a solvate or pharmaceutically acceptable salt thereof, X ^- is Cl ^- or BF ₄ ^- with A cyclic sulfonium salt compound or a stereoisomer , a solvate or a pharmaceutically acceptable salt thereof. The cyclic sulfonium salt compound according to any one of claims 1 to 2, or a stereoisomer , solvate or pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or -CH ₂ OH. Or — (CH ₂ ) ₂ —CH ₂ OH, and R ² is a C ₁ -C ₁₃ alkyl group, or a benzyl group, o-, m- or p-halobenzyl group, o-, m- or p-nitro. benzyl, o-, m- or p- methylbenzyl, o-, m- or p- trifluoromethylbenzyl group, a hydroxymethyl benzyl group, a naphthylmethyl group or a pyridylmethyl group, X ^- is Cl ^- or BF ₄ ^- cyclic sulfonium salt compound or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof consists a. It contains the cyclic sulfonium salt compound according to any one of claims 1 to 6 or a stereoisomer , solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition for inhibiting α-glucosidase. Diabetes, diabetic complication comprising the compound or stereoisomer , solvate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier. Composition for prevention or treatment of infectious disease, obesity, dyslipidemia, or hypertension. A health food for inhibiting α-glucosidase, comprising the compound according to any one of claims 1 to 6, or a stereoisomer , solvate or pharmaceutically acceptable salt thereof.